Epithelial ovarian cancer, the fourth leading cause of cancer deaths in American women, is currently classified by surgical and histologic appearance. However, the predictive value of this classification is limited. The risk of epithelial ovarian cancer increases with the number of ovulatory events. It is now thought that different ovarian tumors are derived from a single ovarian surface epithelial precursor cell with the degree and pattern of differentiation determined by combinatorial expression of homeobox genes normally involved in differentiation of the female genital tract. This aberrant differentiation occurs in association with histology-specific genomic aberrations, genomic instability, and resultant chromosomal changes, and may be triggered by prolonged abnormal or excessive exposure of surface epithelial cells to autocrine/paracrine stimulation by sex steroids and other growth factors. As the disease progresses, activation of kinase pathways and continued abnormal autocrine/paracrine stimulation contribute to genomic instability but also identify potential targets for novel therapeutic intervention.